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Objective To assess the efficacy of desmopressin, alarm, desmopressin plus alarm, and desmopressin plus anticholinergic agent (AA) therapy in the management of paediatric monosymptomatic nocturnal enuresis (MNE) using a network meta-analysis. Materials and methods We searched the electronic databases PubMed, Cochrane Library, EMBASE and Web of Science from inception to 1 March 2018. Randomized controlled trials (RCTs) that compared desmopressin, alarm, desmopressin plus alarm, and desmopressin plus AAs were identified. The network meta-analysis was conducted with software R 3.3.2 and STATA 14.0. Results Eighteen RCTs with a total of 1 649 participants were included. The meta-analysis results showed that complete response (CR) and success rates with desmopressin plus AAs were higher than with desmopressin or alarm monotherapy. Success rates for desmopressin plus alarm therapy were higher than for alarm monotherapy. No obvious difference was observed between desmopressin plus AAs and desmopressin plus alarm therapy with regard to CR rate and success rate. The relapse rate with alarm monotherapy was much lower than with desmopressin monotherapy. Adverse events seemed to be infrequently and tolerable for all treatments. The ranking probability results were as follows: desmopressin plus AA ranked first for the outcomes of CR and success, desmopressin plus alarm therapy ranked first for mean number of wet nights per week, and alarm therapy had the lowest relapse rate. Conclusions The network meta-analysis showed that desmopressin had similar efficacy to alarm therapy but a higher relapse rate. Desmopressin plus AA therapy was associated with better efficacy than and a similar relapse rate to desmopressin monotherapy. Desmopressin plus alarm therapy was similar to both desmopressin and alarm monotherapy in efficacy. All treatments, including desmopressin plus AAwere associated with tolerable adverse events; however, additional high-quality studies are needed for further evaluation of these treatments.

Objective: • To determine whether muscarinic receptor antagonism affected stretch-induced release of ATP. Materials and methods: • Mucosal strips, dissected from Guinea pig (male, 450g; n = 10) urinary bladder, were placed in horizontal organ baths and superfused with Ca2+-free Tyrode’s solution. • Superfusate samples were taken pre- and post- intervention (rapid stretch or relaxation) and ATP concentration quantified using a luciferin-luciferase assay. • The effect of muscarinic acetylcholine receptors antagonism on ATP release was assessed by addition of methoctramine (1 μM) and 4-DAMP (10 nM). Results: • Rapid stretch (0 to 13.3 ± 1.2 mN; no. strips = 20) increased [ATP] in the superfusate to a median three-fold increase over basal levels. • Following a period of equilibration, tension in the mucosal strips relaxed until it had reached a new steady-state after 60 minutes and stretch was repeated. In the presence of 4-DAMP (10 nM) or methoctramine (1 μM), [ATP] following stretch reduced to 61% and 20%. By contrast, [ATP] from mucosa-matched controls, perfused with vehicle, increased in response to stretch by 391 and 1500%, respectively. • Rapid relaxation also stimulated ATP release. This release did not appear to be sensitive to 4-DAMP or methoctramine. Conclusion: • An alteration of resting mucosal tension is the key determinant of ATP release, as ATP is released from the mucosa in response to both stretch and relaxation. • Muscarinic receptor antagonism inhibits stretch-evoked ATP release from bladder mucosa, suggesting anti-cholinergic agents used to treat human lower urinary tract pathologies act on urothelial muscarinic receptors.

BJU Int 2012; 110: E381–E386. Objectives: To assess the efficacy of desmopressin plus oxybutynin and compare two starting dosages of desmopressin (120 and 240 g) in a randomized, double-blinded, placebo-controlled trial for children with monosymptomatic nocturnal enuresis (MNE) resistant to desmopressin. The predictive factors of children with MNE responsive to desmopressin and combination therapy were also evaluated. Patients and Methods: Our sample included 206 patients aged between 6 and 13 (mean age 10.6 2.9 years), 117 males. All patients were required to have MNE. The patients were randomly divided into two groups: the first group was given oral melt 120 g and the second group 240 g, for 2 weeks. All patients who had experienced failure of treatment with sublingually administered desmopressin alone were given either desmopressin plus 5 mg oxybutynin or desmopressin plus placebo in a randomized, double-blinded trial for 4 weeks. As predictive factors, bladder volume and wall thickness index, nocturnal polyuria and voiding latency were considered. Results: There was no significant difference between the 120 g and 240 g patients in terms of response. The oxybutynin group showed a higher rate of full and partial responses (45% success) compared with the placebo group (17% success), P 0.01. The responders to combined oxybutynin and desmopressin had significantly lower bladder volume and wall thickness index than the other patients. Conclusions: Our findings highlight that anticholinergic agents may play an important role for a subset of children with enuresis who have a restricted bladder capacity and thickened bladder wall. Ultrasonographymeasured bladder variables can provide useful predictive clues for MNE. Predictive factors can help to differentiate treatment subtypes and guide clinical management in primary nocturnal enuresis. Editorial Comment: This study reviews 206 patients with MNE, and their responses to 2 different doses of desmopressin and a combination of desmopressin and oxybutynin. Despite seemingly homogeneous presenting symptoms, children who responded best to desmopressin had greater nocturnal urine production. Those who responded best to a combination of oxybutynin and desmopressin had lower bladder volume wall indices (defined by maximum measured bladder volume divided by measured mean bladder wall thickness). This study provides an algorithm that helps guide the management of the large volume of pediatric MNE cases we see, which at first glance appear homogeneous but may in fact represent 2 groups, ie 1 with higher nighttime urine production and 1 with a tendency toward overactive bladder.

Urinary incontinence affects an estimated 20-33% of adults the USA and 55% of the country's elderly [1], having a more substantial impact on the physical and mental dimension of quality of life than other common chronic diseases. Muscarinic receptor antagonists, including oxybutynin, tolterodine, trospium chloride, darifenacin, and solifenacin, are front-line therapies for overactive bladder (OAB), with an efficacy of 65-75% in reducing major symptoms. Strategies to increase the therapeutic index have included behavioural therapy, flexible dosing, and dose escalation, as well as newer formulations that reduce anticholinergic side-effects. Among approved OAB agents, the oxybutynin transdermal-delivery system has been associated with a lower incidence of dry mouth than immediate- and extended-release formulations of traditional agents. With a low propensity for drug interactions and dry mouth, it is a likely candidate for older patients taking multiple medications. The transdermal patch bypasses systemic and first-pass metabolism, avoiding higher plasma concentrations of the active metabolite (N-desethyloxybutynin) thought to be associated with dry mouth symptoms. Anticholinergics have a significant role to play in the management of OAB; newer drugs targeted toward muscarinic receptors, and novel delivery systems, continue to increase the therapeutic index for this condition.

OBJECTIVE To examine the effectiveness and tolerability of multiple intravesical instillations of 10 nmol/L resiniferatoxin in patients with detrusor overactivity (DO) refractory to anticholinergic agents, as not all these patients are successfully treated by one such instillation. PATIENTS AND METHODS The study included 53 patients with DO from neurogenic (NDO, 10), previous bladder outlet obstruction (BOO, 20) or idiopathic cause (IDO, 23) and who were refractory to anticholinergic agents. Patients received three to four instillations of 10 nmol/L resiniferatoxin, as outpatients. The International Prostate Symptom Score and quality-of-life index were recorded, and a video-urodynamic study conducted at baseline and 3 months after treatment. The therapeutic results and urodynamic variables were compared among patients with different causes of DO. RESULTS Four patients withdrew from the study after the first instillation because of urinary tract infection or severe pain on urination, leaving 49 who completed at least three instillations. The overall results were an excellent response in 17 patients (35%), improvement in 13 (27%) and failure in 19 (39%); the treatment was deemed a success (excellent or improved) in 16 of 20 with previous BOO, 11 of 19 with IDO, and only three of 10 with NDO (P = 0.011). Patients had significant improvements in the storage symptom score, total symptom score and quality-of-life index after treatment. The cystometric capacity and the postvoid residual were significantly greater and voiding efficiency significantly less after treatment. DO during the urodynamic study was absent in 12 patients after treatment. CONCLUSIONS Multiple intravesical instillations of 10 nmol/L resiniferatoxin are effective in treating patients with DO refractory to anticholinergics.

OBJECTIVE To investigate the potential utility of botulinum toxin A (BoNT-A) bladder injections in patients with radiation cystitis and bacillus Calmette-Guerin (BCG)-induced chemical cystitis. PATIENTS AND METHODS In all, six patients with refractory radiation cystitis were treated with 200 U bladder BoNT-A injections and two patients with refractory cystitis after intravesical BCG therapy were treated with 100 U bladder BoNT-A injections. All the patients were refractory to anticholinergic agents. Under sedation or local anaesthesia, BoNT-A was injected through a cystoscope into 20 sites submucosally in the trigone and floor of the bladder. RESULTS There were no side-effects or retention after BoNT-A injection. In five of the six patients with radiation cystitis there was a moderate to significant improvement; the mean (sd) bladder capacity increased from 105 (25) mL to 250 (35) mL and the urinary frequency decreased from 14 (2) to 11 (1) episodes per day. In the two patients with BCG cystitis both reported significant symptomatic improvement; the mean (sd) bladder capacity increased from 110 (23) to 230 (23) mL, the urinary frequency decreased from 16 (1) to 12 (1) episodes per day, and using a 10-point visual analogue pain scoring system, the perceived pain score decreased from 8 to 2. Microscopically, the bladder tissue at 1 month after BCG injection showed marked acute and chronic inflammation with eosinophilic infiltration and focal granulomatous formation. At 2 months after BoNT-A injection, there was only a mild degree of chronic inflammation with few eosinophils. CONCLUSION These preliminary results suggest that BoNT-A injected into the bladder is a promising treatment for patients with refractory radiation and BCG cystitis.

Objective To present the long-term results of bladder autoaugmentation in myelodysplastic children with low compliance neurogenic bladders who failed attempts at medical management, including clean intermittent catheterization (CIC) and pharmacological bladder relaxation. Patients and methods Twenty-one patients with a neurogenic bladder after myelomeningocele operations (mean age 9.5 years, range 3–16) underwent autoaugmentation; 12 children were paraplegic and hydrocephalic, and were treated by insertion of a ventriculoperitoneal valve. All patients had low-compliance neurogenic bladders confirmed urodynamically. Ten patients had vesico-ureteric reflux (VUR) and eight had dilated upper urinary tracts with no reflux. All patients had been treated pre-operatively using CIC and anticholinergic agents, with no success. Results Of 21 children treated surgically, 17 were assessed urodynamically and examined to determine the condition of the upper and lower urinary tract. The follow-up ranged from 3 months to 8 years (mean 6 years). In 13 patients the bladder capacity increased by ≈60 mL and in 14 the intravesical pressure decreased by ≈65 cmH2O. Fourteen children were continent using CIC (from 3- to 4-hourly); in the six patients with VUR the reflux resolved in two, decreased in two and remained unchanged in two. Of eight patients with dilated upper tracts but no reflux, seven improved. There was no improvement in bladder capacity in four patients and no reduction in intravesical pressure in three. Two patients underwent enterocystoplasty (one ileocystoplasty and one colocystoplasty) with good results. Two children needed anticholinergic agents after autoaugmentation. Conclusions Autoaugmentation effectively reduces high intravesical pressure and provides a sufficient increase in bladder capacity with a concomitant improvement in urodynamic values. The present method allows the extent of the surgical procedure to be limited to the extraperitoneal space and thus maintains all of other options. Bladder autoaugmentation is a reasonable alternative to enterocystoplasty in selected patients.

OBJECTIVE To assess the safety and efficacy of tolterodine tartrate prescribed to children who previously failed to tolerate oxybutynin chloride. PATIENTS AND METHODS We reviewed 34 children, followed for>1 year, who were prospectively crossed-over from oxybutynin to tolterodine because of side-effects. The initial diagnosis was dysfunctional voiding in 31 patients. All patients were placed on a behavioural modification protocol. When their symptoms did not improve after 6 months, treatment with an anticholinergic agent was considered. Urodynamic studies were conducted in 20 patients, confirming uninhibited contractions in 19. The remaining 14 patients were empirically started on antimuscarinic or anticholinergic agents. The 34 patients were treated with oxybutynin for a median (range) of 6 (2–84) months. When significant side-effects were reported, they were crossed over to tolterodine. The efficacy of tolterodine was assessed as defined by the International Children's Continence Society, with tolerability assessed and side-effects documented using a questionnaire. RESULTS The mean age at the first dose of tolterodine was 8.9 years; the dose was 1 mg twice daily for 12 patients and 2 mg twice daily for 22. The median treatment with tolterodine was 11.5 months, with 20 (59%) patients reporting no side-effects; six described the same but tolerable side-effects as with oxybutynin. Eight patients discontinued tolterodine because of side-effects after a median (range) of 5 (1–11) months. The efficacy of tolterodine was comparable with that of oxybutynin, as reported by the questionnaire and voiding diaries. The reduction in wetting episodes at 1 year was> 90% in 23 (68%), more than half in five and less than half (or failure) in six patients. CONCLUSION Tolterodine is tolerated well in children. In this subgroup of patients who could not tolerate oxybutynin, 77% were able to continue tolterodine treatment with no significant side-effects.